PROJECT SUMMARY/ ABSTRACT Targeted therapies to cancers, such as vemurafenib for melanoma, hold enormous promise for treatment, yet the emergence of therapy-resistant tumors presents a significant barrier to cures. In the parent U01 grant, we proposed a multi-faceted approach combining new experimental techniques, statistical analysis, and theory to understand the origin of these rare, transient drug-resistant cell states and devise strategies to control them. Our work related to the parent U01 has demonstrated that transcriptional plasticity in rare individual melanoma cells strongly associates with resistance. These new mechanisms of resistance, which depend on rare cells deviating from the population average, present new opportunities for therapeutic targeting; however, these cellular states are yet uncharacterized, limiting our knowledge of how to control and ultimately eradicate these cells. In the current administrative supplement, we focus on the molecular specificity of small molecule inhibitors targeting the RAF/MEK/ERK pathway which as noted above have become a potent tool of precision medicine, but their clinical efficacy is highly variable in diverse RAS and BRAF mutated cancers. Even in susceptible cancers, they rarely give strong responses. We employ tools of molecular modeling, dynamics, and docking to relate how drug bonding can stabilize alternative conformations of kinases and how such conformations can differentially stabilize upon dimerization occurring through protein-protein interactions. Studying the causes for resistance, which include `paradoxical' ERK pathway activation by RAF inhibitors, has revealed complex molecular adaptations in RAF kinases and the ERK signaling network.